Pathogens in biofilms are more resistant to harsh environmental stresses such as antibiotics and the host immune system. Prevention of biofilm formation is critical to advancing therapeutic treatments against infectious diseases. Oral biofilm is important for periodontal diseases in which pioneers provide substrates allowing colonization of subsequent pathogens. Oral bacterial interactions, especially coaggregation between pioneering colonizers (such as mitis group streptococci, MGS) and pathogenic species (such as Porphyromonas gingivalis or Fusobacterium nucleatum), are important for periodontal diseases. We have identified a Streptococcus sanguinis two-component system (TCS) gene that is responsible for increased adherence with P. gingivalis and F. nucleatum. We propose an integrative study of this TCS regulon and related gene functions by systems biology. To characterize the TCS regulon, the gene expression profiles will be examined using microarray technology. The DNA binding sites will be identified by ChIP-seq. To examine gene functions in biofilm, the TCS regulated gene mutants will be collected from a comprehensive gene mutant library. Bacterial interaction of these mutants with oral pathogens will be systematically examined to identify biofilm genes by confocal microscopy. The biological functions of these genes will be studied as a whole to understand the relationship of the TCS and the biofilm genes.